This report summarizes studies aimed to characterize pharmacologically, hemodynamically and biochemically DA-1 (fenoldopam) and DA-2 (quinpirole) dopamine receptor agonists in anesthetized rats. Fenoldopam (20 micrograms/kg/min i.v. over 15 min) and quinpirole (10 micrograms/kg/min i.v. over 15 min) share the common property of decreasing mean carotid artery blood pressure by lowering peripheral vascular resistance. Fenoldopam increased mesenteric and renal blood flows whereas quinpirole decreased the former blood flow, but enhanced the latter. These effects of quinpirole were antagonized selectively by S-sulpiride, but not SCH 23390; however, with fenoldopam the reverse was found. In chlorisondamine-pretreated rats with blood pressure supported by vasopressin, fenoldopam, but not quinpirole, caused hypotension. In nephrectomized rats, the blood pressure effects of fenoldopam (assessed as area under the infusion time-response curve) were more pronounced than in sham-operated controls. The hypotensive effects due to an i.v. bolus injection of fenoldopam, but not to acetylcholine, histamine, salbutamol or quinpirole, were significantly inhibited in rats pretreated with an infusion of fenoldopam. In pithed rats, quinpirole reduced the pressor responses to electrical stimulation of the spinal cord without affecting those to exogenous norepinephrine, angiotensin II or 5-hydroxytryptamine which, on the contrary, were inhibited by fenoldopam. The plasma renin activity (in intact rats) was reduced by quinpirole, but elevated by fenoldopam. The latter effect also occurred in pithed rats and was blocked by SCH 23390. Quinpirole lowered heart rate, whilst fenoldopam produced tachycardia. These effects of quinpirole and fenoldopam were significantly inhibited by S-sulpiride and SCH 23390, respectively. In chlorisondamine-pretreated rats quinpirole failed to change heart rate whereas fenoldopam still increased it. In conclusion, these results indicate that DA-1 and DA-2 dopamine receptor agonists can be easily discriminated on the basis of their cardiovascular profiles.

No abstract

In normotensive anesthetized rats, 15-min IV infusions of quinpirole (2.5-40.0 micrograms/kg/min) produced dose-related, rapidly appearing, and long-lasting decreases in mean carotid artery BP and HR. Hemodynamically, the hypotensive effects of quinpirole (10.0 micrograms/kg/min) were due to a fall in total peripheral vascular resistance inasmuch as CO did not undergo significant changes. Mesenteric, hindquarter, and renal blood flows were, respectively, reduced, unchanged, and increased by quinpirole; thus, the renal vascular resistance fell more than either the total peripheral or hindquarter vascular resistance. Biochemically, the hypotensive effects of quinpirole were accompanied by a decrease in the plasma level of norepinephrine and plasma renin activity. The peak fall in blood pressure produced by quinpirole was not significantly modified by atenolol, idazoxan, ranitidine, SCH 23390 (DA1 dopamine receptor antagonist), enalapril, or SK&F 100273 (V1 vasopressin receptor antagonist), but was entirely blocked by S-sulpiride or removal of autonomic nerve drive to the cardiovascular system with chlorisondamine. The effect of quinpirole on systemic and regional vascular resistances was antagonized by S-sulpiride. Furthermore, SK&F 100273 prevented the fall in mesenteric flow produced by quinpirole. Intracerebroventricular injection of quinpirole (10.0 micrograms/kg over 2 min) in saline- or SK&F 100273-pretreated rats produced the same hypotensive effects as an identical IV dose of the compound. In pithed rats, quinpirole (10 micrograms/kg/min IV over 15 min) decreased pressor responses to electrical stimulation of spinal cord outflow without affecting those to exogenously injected angiotensin II, B-HT 920, cirazoline, norepinephrine, or 5-hydroxytryptamine. This inhibitory effect was antagonized by S-sulpiride. The bradycardia produced by quinpirole in intact rats was mediated by the autonomic nervous system inasmuch as it was slightly modified by bilateral vagotomy, partly reduced by atenolol, and entirely prevented by pithing even when the low HR of the last preparation had been raised by IV infusion of isoprenaline. Furthermore, S-sulpiride, but not SCH 23390 or idazoxan, antagonized this effect. In pithed rats, quinpirole similarly inhibited the tachycardic responses elicited by electrical stimulation of either the spinal cord outflow (preganglionic) or postganglionic cardioaccelerator nerve fibers. This effect of quinpirole was susceptible to S-sulpiride but not idazoxan blockade. Finally, in conscious spontaneously hypertensive rats (SHR) but not in normotensive rats, quinpirole (10 micrograms/kg/min IA over 15 min) lowered blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)

Vascular NK-1 and NK-2 tachykinin receptors in the rat and the guinea pig were characterized pharmacologically by using available agonists and antagonists exhibiting varying degrees of selectivity for these receptors. Because the anesthetized guinea pig has unusually low blood pressure, these animals were pithed and vagotomized and infused, throughout the experimental procedure, with norepinephrine (6 micrograms/kg/min). This treatment raised their blood pressure to a level appropriate for the determination of dose-hypotensive response curves. The NK-1 receptor agonists substance P (SP) and septide (0.004 to 1 microgram/kg iv) decreased carotid artery blood pressure in a dose-dependent manner in both species, but they were more potent (13- and 33-fold, respectively) in guinea pigs than in rats. The NK-2 receptor agonist [beta Ala8]-NKA(4-10) (0.06 to 1 microgram/kg) also dose-dependently lowered blood pressure in the pithed guinea pig with noradrenaline-supported blood pressure, although it failed to do so in the same rat preparation. RP 67580, a selective NK-1 antagonist, antagonized the SP- or septide-induced hypotensive response in rats, but not in guinea pigs. Conversely, RPR 100893, a novel NK-1 receptor antagonist chemically related to RP 67580, dose-dependently inhibited hypotension induced by SP, and even more, that induced by septide only in guinea pigs. In the latter species, neither RP 67580 nor RPR 100893 affected decreases in blood pressure induced by [beta Ala8]-NKA(4-10). These decreases were, however, inhibited by the NK-2 receptor antagonist SR 48968. The selectivity of this compound for the latter receptor was confirmed by its failure to affect SP- or septide-induced hypotension in either guinea pigs or rats. These results confirm that the hypotensive responses to SP and septide are mediated by NK-1 receptors in the two species studied. However, functional NK-2 receptors appear to be present in the vascular bed of the guinea pig but not that of the rat, since in the former species the hypotensive responses induced [beta Ala8]-NKA(4-10) were inhibited by SR 48968 but not by the NK-1 receptor antagonists studied. This conclusion is, to our knowledge, drawn here for the first time from clear-cut pharmacological results.

The intestinal perfusion technique was used in 10 healthy subjects to measure the effects of pentagastrin (PG) on jejunal and ileal net and unidirectional movements from two isotonic solutions, one of which was glucose-free (solution I) and the other contained 30 mM glucose (solution II); in five further subjects, the effect of the pentapeptide on intrajejunal transit time was assessed, (a) In the jejunum, PG had no effect on net movements of water and electrolytes from solution I, whereas it significantly reduced net absorption of water, sodium, potassium and chloride from solution II, without affecting the absorption of glucose itself, (b) Both jejunal unidirectional fluxes of water, sodium and potassium were reduced by pentagastrin, whatever the solution infused; but, in the presence of glucose, the insorption (lumen to blood flux) of water and electrolytes was predominantly decreased, (c) PG did not modify intrajejunal transit time of fluid, (d) Ileal transport of water and ions was not affected by PG. The mechanism of the action of PG is discussed in the light of current knowledge of transport mechanisms across the intestine, and the possibility is raised that it may act through a reduction of the size of the ‘pores’ of the plasma membrane of the enterocyte. Finally, it is suggested that overproduction of gastrin, as seen in the Zollinger-Ellison syndrome, may play a direct role in the watery diarrhea sometimes observed in this disease.